Ischemic cardiovascular disease, specifically myocardial infarction (MI), is the leading cause of morbidity and mortality in Western society. There are clear gender-based differences in cardiac function and electrophysiology that influence the two major sequelae following MI: heart failure (NF), and susceptibility to arrhythmias. In women, MI is uncommon prior to menopause and postmenopausal estrogen replacement therapy decreases its incidence. These beneficial effects of estrogen have been attributed previously to indirect effects on classic risk factors. However, estrogen is now recognized to have direct effects on cardiovascular cells that are central to its beneficial effects on cardiovascular disease. Estrogen's effects are mediated by receptors that act as ligand-activated transcription factors. Two such receptors are currently known, ERALPHA, and the recently discovered ERbeta. We have developed and reported a series of novel murine models that provide unique tools for pursuing mechanistic questions related to the pathophysiology of cardiovascular diseases. These include a mouse model of MI and a mouse cardiac electrophysiology (EP) model. We now present preliminary data from murine models demonstrating: (a) gender- based differences in cardiac electrophysiology, susceptibility to ventricular arrhythmias, and post-MI cardiac remodeling; (b) alteration in cardiac performance and electrophysiology in ERalpha (ERalphaKO) and ERbeta (ERbetaKO) knockout mice; (c) expression of both ERalpha and ERbeta and (d) ER-dependent effects on gene expression in cardiomyocytes. Taken together, these data identify the heart as a novel target organ for the direct effects of estrogen and form the basis for this Project's central hypothesis: Estrogen receptors regulate left ventricular remodeling and susceptibility to arrhythmias following myocardial infarction. We propose to test this hypothesis by pursuing two specific aims: Specific Aim 1: Investigation of the role of estrogen receptors an the effect of estrogen receptor modulators, including the SERM raloxifene, on left ventricular remodeling following myocardial infarction, using wild-type, ERalphaKO and ERbetaKO mice, and Specific Aim 2: Investigation of the role of estrogen receptors and the effect of estrogen receptor modulators on arrhythmias following myocardial infarction, using wild-type, ERalphaKO and ERbetaKO mice. These in vivo studies explore the molecular pathways that mediate gender-based and hormonal influences on cardiac remodeling and arrhythmias following MI. In addition, they provide a conceptual bridge from the genetic and clinical studies (Projects 1 and 2) to the other basic science projects (Projects 4 and 4) of this SCOR in ischemic heart disease.